Pyrazolidone derivatives substituted on the 4 position with pectin or algin

ABSTRACT

HYDROGEN BONDED COMPOUNDS OF THE STRUCTURE:   1,2-DIPHENYL,3,4-(-O-Z-),4-(CH3-CH2-CH2-CH2-),5-(O=)   PYRAZOLIDINE   WHEREIN Z IS A COMPOUND OF THE GROUP SELECTED FROM ALGIN AND PECTIN AND THE METHODS FOR THE PREPARATION OF THE AFORESAID COMPOUNDS. THE COMPOUNDS ARE USEFUL IN ACHIEVING AN ANTI-INFLAMMATORY EFFECT.

United States Patent C US. Cl. 260-2095 2 Claims ABSTRACT OF THEDISCLOSURE Hydrogen bonded compounds of the structure:

wherein Z is a compound of the group selected from algin and pectin andthe methods for the preparation of the aforesaid compounds. Thecompounds are useful in achieving an anti-inflammatory efrect.

This application is a division of applicants then copending application,Ser. No. 856,508, filed May 14, 1969, now US. Pat. 3,629,282, which wasa division of applicants then co-pending application, Ser. No. 691,197,now US. Pat. 3,487,046, filed Dec. 18, 1967, which was acontinuation-in-part of applicants then co-pending application, Ser. No.362,393, filed Apr. 24, 1964, now abandoned, which was acontinuation-in-part of applicants then co-pending application, Ser. No.121,796, filed Apr. 24, 1961, now abandoned.

The present invention relates to new and novel compounds prepared frompyrazolidone, their process of manufacture and their pharmaceutical andtherapeutic usage in both human and veterinary medicine. In particular,the present invention is concerned with mono and polyglycosidiccompounds, polyoxyethylene compounds and hydrogen bonded compounds of3,5,-dioxo-1,2,-diphenyl-4n-butyl pyrazolidine. These compounds have atherapeutic and pharmacologic utility which is unique and possessing ofadvantages over the older therapeutic agents.

A problem in the treatment of arthritis and certain of the relatedpathologic states is one which is constantly present in the practice ofboth human and veterinary medicine. While many pharmacologic approachesto therapy have been suggested and many chemical entities synthesizedand described as having a therapeutic effect, the clinician must stillmeet the problem of deciding upon the specific drug to treat a specificpatient who presents symptoms which fall into the accepted pathologicalcriterion for these diseases.

In recent years, a pyrazolidone derivative, namely 3,5-dioxo-1,2-diphenyl-4-n butyl pyrazolidine, has been utilized withclinical success in the treatment of various arthralgic states despite anumber of inherent limitations. The common name for this compound isphenylbutazone. Phenylbutazone has been demonstrated to have a markedcapacity to raise the pain threshold in laboratory animals, as well asexerting an antipyretic effect. Phenylbutazone exhibitsanti-inflammatory properties in animals similar to Cortisone, andalthough it has been shown that its ac- 3,790,558 Patented Feb. 5, 1974tion is not mediated through the pituitary-adrenal cortex axis, itcauses sodium retention which may lead to edema. Tissue respirationstudies have shown that the oxygen consumption of brain tissue islowered as is the utilization of glucose by the tissues.

It has been demonstrated that phenylbutazone is slowly metabolized inman. The rate of biotransformation varies with diiferent subjectsalthough the range has been postulated to be from 10 percent to 40percent a day.

It is well known that virtually small doses, as for example, 10 mg.percent in the blood stream, is required for the anti-flammatorybeneficial therapeutic eifect to be observed in patients with rheumatoidarthritis.

Phenylbutazone is extremely insoluble in water. In order to achievesolubility so that it may be administered and absorbed orally or byinjection, the alkali metal salt has been formed. The sodium salt hasreceived preference. The sodium salt of henylbutazone thus formed, andits solution, are stable only in the more alkaline pH range because ofthe weak ionic strength of the pyrazolidine derivative and breakdown ordecomposition occurs when the pH of the medium is less than 8.2.

This decomposition at a critical pH of 8.2 is highly significant sincethe physiological pH range is rarely above pH 7.6 and almost alwaysbetween the range of pH 7.2 and pH 7.4. Moreover, when this drug, (viz.the sodium salt), is administered orally, there is a virtually completeand instantaneous decomposition by the stomach contents which rarely, ifever, rise above pH 4 and most often is at pH 1 to 2. This decompositionof the alkali metal salts, moreover, results in an insoluble basesubstance which is then variably absorbed at a level limited to thesolubilityproduct transfer, which conforms to the rates expressed by thelaw of mass action relating to substance difficultly soluble anddecomposable in a dynamic system.

The consequences of this variable absorption and insolubility are bestobserved by the high dose range required for therapy. As much as 1 gm.has been commonly used. Larger amounts are employed for the treatment ofcertain patients having more serious disease.

The first eifect observed, as a result of the precipitation of the basematerial of the sodium, salt in the stomach, is a delayed onset ofeffect until therapeutic blood levels are reached. This delay of onsetof eflect is readily apparent to the clinician and is described by himas the period of therapeutic latency. This latent therapeutic period isabsent when the drug is administered parenterally, thus establishingthat this phenomenon is due to the variable absorption which results inineffective blood levels or until enough of the drug accumulates in theblood to exceed the threshold level of activity. Thus, with abiometabolic destruction rate of from 10 percent to 40 percent per day,the factor of the rate of development of the therapeutic blood level isgoverned only by the amount being absorbed in excess of thisdestruction.

Still another inherent limitation has arisen with the use ofphenylbutazone which has caused the caution the use must be enjoinedwith a careful follow-up of the patients blood picture as well as arestriction against long-term use in effective upper level doses, andthis limitation is one of a blood dyscrasia (agranulocytosis). Liverdamage has also been suggested.

The products of the present invention, by rendering 3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine either more soluble inphyisologic media or by the control of the rate of absorption throughalteration of the physical transport mechanisms involved by controllingthe availability of the drug for absorption in accord with the demand ofthe dynamic system, avoids the above limitations of insolubility and/orvariable absorption. Thus, the products of our invention may be given inlower dosage to achieve the same level of therapeutic effect, since theyare either more soluble and/or more predictable in absorption, and thedosage, administered to the individual patient may therefore becontrolled so as to supply that quantity which is metabolized during agiven period without permitting excess to accumulate and cause itsnoxious toxic effect on the patient.

The individual determination of the rate of metabolism in the individualpatent presents no problem since the metabolized compound is excretedvia the kidney and reliable as well as sensitive methods of analysis areavailable and presently being practiced by the laboratory technician inboth hospitals and private physicians laboratories.

Therefore an effective, as well as reliable, means of avoiding thetherapeutic limitations inherent in the compound phenylbutazone and itsconventional basic salts may be conveniently and readily avoided by useof the present products.

Phenylbutazone glycoside is a solid white crystalline substance preparedthrough the general reaction of the alpha-halogen monoglycose and themetallic salt of 3,5- dioxo-1,2-diphenyl-4-n-butyl pyrazolidine. Whileany glycose may be used, we have found it is preferable to use a memberof the class of sugars known as trioses, tetyoses, pentoses and hexoses.Although the higher glycoses may be used problems of isomerizationrestrict and limit certain aspects of the synthetic procedure. For thisreaction, the appropriate sugar halide or alpha-halogen glycose may beeither the fluoride, chloride, bromide or iodide deriavtive although itis preferred to use the bromide, chloride and iodide derivatives underpractical synthetic conditions.

The reaction may be carried out in either aqueous, alcoholic orhydroalcoholic media, and may also be conducted in any other inertorganic medium which does not interfere with the course of the reaction.It has been found that an alcoholic medium is preferred since thecomponents are obtained in a state of purity requiring little or nopurification as well as facilitating the separation of the product ofthe reaction. However, the products resulting after the use of otherorganic or aqueous solvents do not require such a degree of purificationso as to render them therapeutically unusable.

It was found that the addition of small amounts of silver hydroxide, orcopper powder, to this reaction will materially augment both the yieldand the speed of reaction.

When silver hydroxide or copper powder are used as catalysts for thisreaction the range of their concentration to be added is dependent uponthe size of the reaction and will range from 0.01 to 0.10 percent of thereacting weight of the components used in the particular reaction.

The resulting phenylbutazone glyoscide is soluble in water to a greaterextent than phenylbutazone and is stable over the physiologic pH range.It may be administered therefore in a smaller dose to achieve a moreideal therapeutic effect without placing the patient in jeopardy ofinjury which may extend from gastric disturbance to fatal consequences.

Phenylbutazone glucoside is the additional product of glucose andphenylbutazone, which is obtained as a result of the interaction betweenphenylbutazone and an alpha halo glucose, as for example, alpha-bromoglucose. In carrying out this reaction a neutral solvent such asisopropyl is used.

To an isopropyl alcohol solution of alpha-bromo glucose is added astoichiometric equivalent of either an alkaline solution ofphenylbutazone in isopropyl alcohol or a solution of the metallic saltof phenylbutazone in isopropyl alcohol. A catalyst of silver hydroxideor copper powder is utilized to complete the reaction. The glucoside of3,5- dioxo-1,2-diphenyl-4-n-butyl pyrazolidine corresponds to theempiric formula C H N O and analyzes in good agreement with itscalculated theoretical values. This compound is to be distinguished fromthe acetylated glycosidic c mp n s of Morel (Ex perient ae 1 :29 1958)Since Morels compounds were not absorbed and had no activity. It is ofinterest to note that the d-acetylated glucoside could not be obtainedfrom Morels synthetic compound because of the extreme lability of theacetylated products. Thus, while the acetylated product has beenprepared and found to be not absorbed in men, the present glucoside, of3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine is desirable by virtue ofits activity.

Polymeric glycose derivatives may also be prepared through the use ofthe omega-halogen polyglycose compound in place of the alpha-halogenmonoglycose and also polyoxyethylene derivatives may be formed throughthe use of the corresponding omega-halogen polyoxyethylene compound.When the omega-halogen polyoxyethylene derivatives are used, thecorresponding polyoxyethylene derivative of3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine results.

Hydrogen bonded chelation complexes may also be prepared. Thesegenerally fall into two fundamental groupings, such as those preparedwith polymeric carbohydrate gums, as for example, pectin, gum guar,algin, gum arabic and gum tragacanth.

New compounds of 3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine may bereadily prepared with anionic exchange resins which are particularlyadapted to this purpose and are condensation products of a phenol,formaldehyde and an alkylene polyamine, the alkylene group of which maybe interrupted NH-- to form alkylene chains of the last two carbon atomsbetween nitrogen atoms. These resins are known in commerce under thetrade name of Amberlite and more particularly as Amberlite-IR, orAmberlite-IRP-58M or Amberlite XE-5'8M and these are marketed by TheResinous Products and Chemical Company, Philadelphia, Pa. Resins of thissame type are also marketed by other concerns under different tradenames. Some of these resins and processes for their preparation aredescribed in US. Pat. No. 2,402,384, issued June 18, 1946, on anapplication of John W. Eastes, entitled, Ion-exchange Polyamine Resinsand the Methods of Preparing Same. Although resins of the classdescribed in the aforesaid patent may be employed, it is preferred touse the anionic exchange resin which is a condensation product ofdihydroxy phenyl didimethyl methane, formaldehyde and tetraethylenepentamine, hereinafter called resin.

When the selected Amberlite exchange resin is reacted with3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine, the resultant compound isformed by attachment of the resin in the 4 position of the pyrazolidinering and the new compound has neither the properties of the freereagents nor that of a simple mixture, nor that of a salt. Thus, forexample, the new compound formed of 3,5-dioxo-1,2-diphenyl-4-n-butylpyrazolidine and Amberlite IRP-58M resin does not exhibit the acidicproperties of the free pyrazolidine compound in its combining power withalkali nor may it be mechanically separated into its component partsthrough extraction with organic solvents, such as benzene or chloroform,as would a simple mixture. Neither does the formed compound ionize aswould a salt and it does not have the electro-physical properties of asalt. The compound resulting from the reaction of the Amberlite IRP-SSMresin with 3,5-dioxo-l,2diphenyl-4- n-butyl pyrazolidine, is a stable,homogeneous product with reproducible and well defined physical-chemicalproperties, which are clearly distinguishable from the conventionalsalts. The new compound contains from 16 to 19 percent of thepyrazolidine moiety and has a sharp melting point of between 211-2l3 C.(with decomposition), which contrasts sharply to the melting point of3,5- dioxo-1,2-diphenyl-4-n-butyl pyrazolidine, which is from 103 to 105C. The new compound is insoluble in water.

The capacity of the resin to combine with 3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine is determined by the pH of thesolution; by electrolyte concentration and by the pKa of the cation.Thus, a compound of the 3,5-dioxo 1,2-diphenyl'4-n-butyl pyrazolidineand the Amberlite XE-58M resin is formed to the extent of 0.6 meq./gm.of resin in dsitilled water but this ratio is doubled so that 1.2meq./gm. of resin results when IM potassium chloride is substituted forthe distilled water.

The infrared spectra of the new compound 4-resin 3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine compound is characteristic forthe new molecule. The characteristic phenylbutazone bands are notpresent in the infra-red spectra of the new compound and there is ashift in the bands characteristic for the resin. This change in theinfrared spectra of the component moieties of the new chelation compoundestablishes not only the identity of the new chelation compound but alsoa new physicalchemical reaction has taken place.

The compound represents a constant ratio of phenylbutazone to resincombined at the 4 position of the pyrazolidine ring. This ratio isconstant and independent of reaction temperatures, concentration ofreagents or stirring time. Thus, when water is employed as a solvent,the ratio of phenylbutazone to resin is 0.6 milliequivalent of3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine per gm. of resin. However,when one molar potassium chloride solution or one molar sodium chloridesolution is substituted for the distilled water, this ratio is doubled,so that a chelation compound representing 1.2 milliequivalents of3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine per gm. of resin isobtained.

6 5.96% nitrogen. Found: 63.21% carbon; 6.21% hydrogen; 6.01% nitrogen.

The compound is moderately soluble in water, alcohol, methanol, ethanol,isopropanol, and insoluble in ether and benzene and is sufiiciently pureafter the first recrystallization to be used in therapy in the form ofeither a tablet, capsule or powder or a liquid preparation such as asyrup or elixir to be administered orally or a solution for parenteraluse.

EXAMPLE 2 In place of the alpha-bromo-glucose used in Example 1 above,there may be substituted the fluoro, chloro and iodo analogues instoichiometric reacting equivalent amounts, of any of the members of theclass of compounds known as trioses, tetroses, pentoses and hexoses. Theremainder of the steps are as described in Example 1 above. Theresulting compounds, however, will differ in physical and chemicalproperties dependent upon the length and nature of the glycose used(viz., triose, tetrose, pentose and hexose).

Similarly, should the various isomeric glycoses within a particulargroup be utilized (in their halogen derivative form), then therespective isomeric derivative of the phenylbutazone will result. Theratios of the reacting products in these instances remain the same andthe steps to be taken are similar to or identical to those described 1nExample 1 above. The properties of the respective compounds aredescribed as follows:

Elemental analysis, percent Carbon H dro on i Empiric M.P., y g N tmgenCompound formula C. Thry Fnd. Thry. Fnd. Thry. Fnd.

Dihydroxypropyl p e yl ta o e 22H26N2O4 1 116-18 69.09 70.10 6.85 6. 627. 3a 6 9 2 Phenyl utaz yt r sl 2s 2aN205 1 187-88 67.30 67.81 6.89 6.01 6. 82 7. 0i 3 Phylbutazone threosrdm.-- CzaHzaNaOs 1 192-94 67. 67.01 6. 39 6. 03 6. 82 7. 21 4 Phenylbutazone Ilb0S 1d9. 24H2aNzO 1 193-9565. 44 65. 01 6. 41 6. 91 6. 36 7. 00

Phenylbutazone arab111os1de. 24H28N20s 1 201-04 65. 44 65. 62 6. 41 6.83 6. 36 6. 41

Phenylbutazone lyxos1de O24H25N206 1 207-10 65. 44 65. 81 6. 41 6. 92 6.36 6. 10 7 Phenylbutazoue xy1os1de.--; C24H28N2Oa 1 208-09 65. 44 65. 836. 41 6. 10 6. 86 6. 15 3 Phenylbutazone mannosrde. 2sHsoNzO1 1 201-0463. 81 64. 01 6. 43 6. 73 5. 96 5. 81 9 Phe y t o e sorboslde C25H3DN2071 187-88 63. 81 64.10 6.43 6. 56 5. 96 5. 51 10- Phenylbutazonegluconate- CzaHszNzOo l 181 59.51 58. 91 6. 6. 61 6. 5. 83 11Phenylbutazone glucuronate ozs soNzon l 206 59. 75 59. 31 6. 02 5. 91 5.57 5. 12 12 Phenylbutazone mannuronate oaHmNzot l 216 59. 75 59. 82 6.02 6. 10 5. 57 5. 15 13 Phenylbutazone g lacturo at ozs soNzon 1 241 59.75 59. 61 6.02 6. 21 5. 57 5. 41

1 Decomposition.

The following examples illustrate the scope of this invention.

EXAMPLE 1 In a round-bottom, three-neck glass boiling flask fitted witha reflux condenser, and an automatic stirring device, place one liter ofisopropyl alcohol to which is added exactly 1/10 molalpha-bromo-glucose. Stirring is started and when solution is achieved,exactly 1/10 mol of the sodium salt of 3,S-dioxo-l,2-diphenyl-4-n-butylpyrazolidine is added in small quantities with continued stirring. Whenall of the sodium salt of 3,5-dioxo-1,2-diphenyl-4-nbutyl pyrazolidinehas been added, 0.3 gm. of freshly precipitated silver hydroxide isadded at once and the mixture slowly heated to refiux temperature.

An almost instantaneous precipitation of sodium bromide occurs whichcontinues until the reaction is complete. After a period of from one totwo hours of refluxing, the mixture is cooled to room temperature andfiltered. The solid material remaining on the filter is washed with asmall quantity (10 cc.) of isopropyl alcohol and added to the filtrate.The alcohol solution thus obtained is concentrated under reducedpressure to ,4 its volume and the whole set aside to crystallize in anice-chest. The crystals obtained are white, needleli-ke, melting withdecomposition at 211-216 C. The compound is the glucoside of3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine corresponding to thechemical composition of C H N O- and analyzes in good agreement with itscalculated theoretical values. Theory: 63.81% carbon; 6.43% hydrogen;

The structural formula of the resultant phenylbutazone glycose compoundsobtained as a result of the methods described in Example 1, above,through Example 5, below, may be represented as:

wherein R is selected from the group consisting of glycoses, having from3 through 6 carbons and polymeric glycoses of which each glycose unithas from 3 through 6 carbons.

EXAMPLE 3 bromo-polygalacturonate, then the resulting compound will havethe empirical formula (C25H30N2 9)m and a melting point of 160 C.(dec.). Microanalysis per micrometric unit reveals: Theory: 59.75%carbon; 6.02% hydrogen; 5.59% nitrogen. Found: 59.43% carbon; 6.01%hydrogen; 5.72% nitrogen.

EXAMPLE 4 In place of the isopropyl alcohol used as a solvent for thereaction described in Example 1, there may be substituted any liquidmember of the class of alcohols corresponding to the general formulaROH, wherein R represents a straight or branched chain alkyl group offrom 1 to 6 carbons.

These alcohols may be used in a ratio of from V2 to 1 liter for eachmolar reaction size. Water may be utilized to replace all or a part ofthe alcohol as the solvent for the reaction and when the reaction mediumis entirely aqueous or when water is present in amounts, in excess ofpercent, the following procedure for isolation of the compound isnecessary. The entire reaction mixture is evaporated to dryness (underreduced pressure) and the residue mixed with ethanol and boiled for fiveminutes, filtered and set aside to crystallize in an ice-chest. Thecompounds resulting may then be used in the preparation ofpharmaceutical dose forms.

EXAMPLE 5 In place of the silver hydroxide used in Example 1, there maybe substituted an equalamount (weight for weight) of finely dividedcopper powder. Either catalyst may be used regardless of whether thesolvent for the reaction consists of alcohol, water or hydro-alcoholicmedia. The ratio for the addition of the copper powder or the silverhydroxide as a catalyst for this reaction is from 0.01 to 0.1 percent ofthe reacting proportions.

EXAMPLE 6 In a round-bottom three-neck glass boiling flask fitted with areflux condenser and a stirring device is placed exactly 1 mol ofmonochloropolyoxyethylene. Stirring is started and small quantities ofsodium of 3,5-dioxo-1,2- diphenyl-4-n-butyl pyrazolidine is added untilexactly one mol of the compound has been introduced into the reactionmedium. The reaction is exothermic and cooling should be employed. Theentire mixture may solidify. The solid mass is then dissolved with theaid of gentle heat, in suflicient ethanol to cause solution of theorganic compound but to leave the insoluble sodium chloride insuspension. The mixture is filtered and the solvent alcohol removed byvacuum distillation and the resulting compound is sufliciently pure tobe used for a pharmaceutical dose form.

It should be noted that the polyoxyethylene derivatives have a varyingmolecular weight depending upon the length of the polyoxyethylene chainused as the reactant and this will determine the ultimate physicalproperties of the respective compounds. Thus, if amonochloropolyoxyethylene compound with a molecular weight of from 200to 600 is used the resulting compound will possess properties which aredifferent from that resulting when the higher molecular weightpolyoxyethylene halogen derivatives are used, as, for example, thosewith a molecular weight of from 600 to 2,000. The properties of typicalolrlnpounds resulting from this reaction are described as o ows:

Percent composi- The structural formula of the polyoxyethylenephenylbutazone compounds may be represented as:

wherein R is a radical selected from the group consisting ofpolyoxyethylene groups having a molecular weight of from 200 through2000.

EXAMPLE 7 In place of the chloro derivative described in Example 6,there may be substituted the fluoro, bromo and iodo derivatives of therespective polyoxethylene. The remainder of the steps are the same asdescribed with the exception of the purification step wherein a higheralcohol should be utilized, as for example, hexanol, when the highermolecular weight compounds are used.

EXAMPLE 8 The reaction as described in Example 6 may also be carried outin the presence of an alcohol solvent or an aqueous or hydro-alcoholicsolvent as described in Example 4 above. Similarly, the ratios of silverhydroxide and copper powder may be utilized as described in Example 5above.

EXAMPLE 9 Chelation coordination compounds are prepared by reactingphenylbutazone with a hydrogen bonding compound. For example, one partof phenylbutazone is dissolved in 500 cc. of isopropyl alcohol, and tothis is added 3 parts of gum guar. The mixture is stirred for one-halfhour and then the solvent is slowly distilled at atmospheric pressure.The mixture is then wetted with 2 parts of water and granulated througha number 16 mesh sieve. The resultant compound is a creamy white powderwhich is dispersible in water and alcohol. It assays in good agreementwith the theoretical values for both the phenylbutazone moiety and thegum guar component. When dispersed in water there is a uniformdistribution of the compound which does not sediment out and which doesnot permit the dialysis of the phenylbutazone radical. Infrared spectralanalysis establishes the presence of a molecular complex.

The preferred ratio between reacting components is from one partphenylbutazone to three parts of gum guar, together a range of from 1:1to 1: 10 may be used. The new compound has the following structure:

EXAMPLE 10 In place of the gum guar described in Example 9 above, theremay be substituted a reacting equivalent weight of pectin, or psyllium,or algin, or dextran, or polyvinylpyrrolidone. The remaining steps arethe same as described in Example 9 above. The preferred ratios ofphenylbutazone to pectin, psyllium, algin, dextran and polyvinylpyr-Percent Physical E-Phenyl- Poly-sac- Solubilityor Compound statebutazone charlde dispersibility Phenylbutazone So1id.- 61. 19 38. 81Insoluble in 1120 and algin. fixed oil; dlsperslble in H20 and ethanol.Phenylbutazone do..- 61. 37 38. 63 Do.

pectin Phenylhutazone do. 73. 51 26. 49 Do.

polyvinylpyrrolidone. Phenylbutazone -do. 65. 54 34. 46 Do.

dextran. Phenylbutazone do 46. 12 53. 88 Do.

gum guar. Phenylbutazone do D0.

psyllium.

The structural formula of the chelating coordination compounds may berepresented as:

GHQ-CHz-CHrH: wherein Z is a chelating compound selected from the groupof compounds such as algin, pectin, gum guar, psyllium, dextran andpolyvinylpyrrolidone.

EXAMPLE 11 In a suitable container fitted with a stirring device isplaced 1 liter of distilled water and to this is added 30 gm. of3,S-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine. The stirring is startedand then 40 gm. of Amberlite XE-58M anionic exchange resin, acondensation product of dihydroxy phenyl dimethyl methane, formaldehydeand tetraethylene pentamine, is added. The mixture is stirred for aperiod of at least 4 hours and then the insoluble material collected ona filter and washed with water. The solid material is dried and groundto a No. 40 standard mesh powder and extracted with two, 100 cc.portions of benzene. The dried powder weighs about 47 grams. Theresultant powder is the new compound of 3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine-4-resin. It has a melting point of from211 to 213 C. (with decomposition). The proportion of3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine in the compound is 0.6meq. of the compound per gm. of resin. This ratio is a constant ratiofor the nonsaline solvent used, and is independent of concentration ofreagents or stirring time.

The new resin phenylbutazone compound has 13.26 percent nitrogen contentand is insoluble in water, benzene and chloroform. The infrared spectrumof the compound obtained as a Nujol mull (see FIG. I) is characteristicfor the new compound. There is an absence of the bands for thepyrazolidine moiety and also there is a shift in the bands of the resinmoiety.

The structural formula of the 4-resin-3,5-dioxo-1,2-diphenyl-4-n-butylpyrazolidine, wherein the resin moiety consists of the condensationproduct of dehydroxy phenyl dimethyl methane, formaldehyde andtetraethylene pentamine, may be represented as:

10 wherein R represents an ion exchange resin which may be any member ofthe class of resins known to the trade as Amberlite resins and which arethe condensation product of dihydroxyphenyldimethyl methane,formaldehyde, and an alkylene polyamine.

EXAMPLE 12 In place of the distilled water used as a solvent in Example11, there may be substituted in the same quantity, molar potassiumchloride solution, molar sodium chloride solution and mixtures of these.The remainder of the steps being the same. The resultant compoundisolated will have a proportion of 1.2 meq. of3,5-dioxo-1,2-diphenyl-4-n-butyl pyrazolidine per gm. of the resin. Thisratio is a constant ratio when the saline solvent is used and isindependent of the proportions of the reagents utilized or the stirringtime. The structure of the compound is the same as described in Example11 above.

EXAMPLE 13 In place of the Amberlite XE-58M resin used in Examples 11and 12, there may be substituted in equivalent quantities, any of theanionic exchange resins which are known to the trade as the Amberliteresins and which are the condensation product of dihydroxy-phenyldimethyl methane, formaldehyde and an alkylene polyamine. The remainderof the steps being the same and the resultant products obtained willcorrespond to that obtained after Example 11, having a chelationcombining ratio of 0.6 meq. of 3,5dioxo-1,2-diphenyl-4-n-butylpyrazolidine per gm. of resin, when water is used as the solvent and 1.2meq. of 3,5-dioxo-1,2-diphenyl-4n-butyl pyrazolidine per gm. of resinwhen a molar potassium chloride or sodium chloride solution is used asthe solvent, as described in Example 12. The structure of the compoundsis the same as described in Examples 11 and 12 above.

EXAMPLE 14 When it is desired to use the glycosides of phenylbutazone,the glycuronic acid salts of phenylbutazone, and the polyoxyethylenederivatives of phenylbutazone, the polymeric chelation complexes ofphenylbutazone and the -4-resin, 3,S-dioxo-l,2-diphenyl-4-n-butylpyrazolidine in therapy, these may be administered in the siutablepharmaceutical dosage forms as for example, in the form of a tablet,capsule, or suppository. A dosage range of from 50 mg. to 1 gram,depending upon the individual patients needs, may be administered inorder to obtain an analgeic, antipyretic and anti-inflammatory anduricosuric effect in the treatment of gout, rheumatoid arthritis, andthrombophlebitis. Because of the unique properties of these compounds,it will be generally found that the preferred dosage range will be from50 mg. to 200 mg. given one to three times daily.

In preparing tablets the desired active ingredient is mixed with anequal amount of diluent, as for example, powdered lactose, or powderedstarch, and to this is added 0.01 part of magnesium stearate and thewhole granulated with a gelatin-water mixture, utilizing a No. 16 meshsieve. The granulation is then compressed into tablets having thedesired size and shape, so that each unit dose will contain from 50 mg.to 200 mg. of the active substance.

Capsules may be prepared 'by filling the appropriate gelatin containerwith the granulation or with a mixture of equal parts of the activeingredient and the diluent. The unit dosage range to be employed whencapsules are manufactured is from 50 mg. to 200 mg. of the activecompound.

Suppositories are manufactured by mixing an appropriate suppositorybase, as, for example, cocoa butter, polyoxyethylene glycol, or mixturesof these with the active ingredient so that each suppository willcontain about 50 mg. to 200 mg. of the active compound per unit dose.

11 There is no need for diluents or binders since the compounds are bothstable and dispersible.

Parenteral solutions are prepared by dissolving the water solublemembers of this series, as for example, phenylbutazone glycoside, inwater-for-injection so that each cc. will contain 100 mg. of the activesubstance. It may be found to be convenient to use a range of from 50mg. to 500 mg. per 00., which may be prepared through adjusting theappropriate solvent-active ingredient-temperature relationships at thetime of manufacture but for ordinary therapeutic use, solutionscontaining 100 mg. per cE'will be found most satisfactory. The solutionsfor parenteral use are packaged in glass ampules and hermeticallysealed. The solutions are stable and may be sterilmed by theconventional techniques as for example, autoclaving.

The compounds of the present invention are therapeutically co-extensivewith phenylbutazone and its metal salts. Thus, they may be employed asanalgesics, antipyretic compounds, anti-inflammatory agents, uricosuricagents and particularly in the treatment of such conditions asrheumatoid arthritis, acute bursitis, thrombophlebitis and gout.

It is not desired to be limited except as set forth in the followingclaims, the above description being by way of illustration of theinvention.

What is claimed is:

1. A hydrogen bonded compound having the formula:

wherein Z is pectin.

2. A hydrogen bonded compound having the formula:

l CHs-CHz-CI-Ig-CH; wherein Z is algin.

No references cited. 25

